Takuya Suyama

Preparation And Characterization Of Phospholanes And Phospha Sugars As Novel Anti-Cancer Agents

Diastereo isomeric erythro and threo forms of 2,3-epoxy-l-phenylphospholane 1-oxides were synthesized from threo and erythro forms of 2-bromo-3-hydroxy-l-phenylphospholane 1-oxides being prepared from l-phenyl-2-phospholene 1-oxide. Alternatively, the epoxides were also prepared by the epoxidation of the 2-phospholene with peroxides such as sodium peroxide and hydrogen peroxide. The reactivity and regioselectivity for the reaction of erythro and threo forms of the 2,3-epoxides with nucleophiles were investigated by using amines, and the reaction afforded 2-amino-3-hydroxy-l-phenylphospholane 1-oxides, which correspond to phospha sugar N-glycosides. 2,3-Dibromo-3-methyl-l-phenylphospholane 1-oxides were first prepared from 3-methyl-l-phenyl-2-phospholene 1-oxide. The prepared phospholanes or phospha sugars were biologically qualified by ΜΤΓ (3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide) in vitro method to find that some of these phosphorus heterocycles or phospha sugars have quite efficient anti-cancer activity for leukemia cells in manners of (i) wide spectra, (ii) high activities, and (iii) high specificities.

Synthesis and evaluation of novel phosphasugar anticancer agents

Starting materials of phosphasugars, 1-phenyl-2-phospholene 1-oxides, were prepared from dienes and phenylphosphonous dichloride (dichlorophenylphosphine). Several substituted novel phosphasugars (3- or 4-halo-substituted)-1-phenyl-2-phospholene 1-oxides as well as 1-phenyl-2-phospholane 1-oxides were prepared from 2-phospholenes. The synthesized compounds were evaluated for their antitumor activities against the leukemia cell lines (U937 and K562) by in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. 2,3,4-Tribromo-3-methyl-1-phenylphospholane 1-oxide showed superior antitumor activity against U937 and K562 cell lines in a comparative evaluation with Glivec. The analysis by flow cytometry implied that 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide induced apoptosis to leukemia cell lines.

Research on Phospha Sugar Analogues to Develop Novel Multiple Type Molecular Targeted Antitumor Drugs Against Various Types of Tumor Cells

Abstract The synthesis and antitumor activity evaluation of new branched phospha sugars, especially deoxybromophospha sugar derivatives or bromophospholanes of 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide (DBMPP: 3) and 2,3,4-tribromo-3-methyl-1- phenylphospholane 1-oxide (TBMPP: 4), against various types of leukemia cell lines as well as the results of the mechanistic studies for characterizing and developing the novel multiple type molecular targeted antitumor agents are reported in this paper. DBMPP and TBMPP were prepared from 1-phenyl-3-methyl-2-phospholene 1-oxide (1). The isomer mixture of phospha sugars prepared were evaluated as novel antitumor agents by MTT in vitro method. DBMPP and TBMPP were characterized by flow cytometry and Western blot analysis and were revealed to be potential antitumor agents against leukemia cell lines of K562 (one type of leukemia cell lines of CML) and U937 (one type of leukemia cell lines of AML) as well as against the various types of leukemia cell lines and also against solid tumor cell lines of stomach, skin, and lung cancers by MTT evaluation and observation by a handstand phase-contrast microscope. The results of the flow cytometry indicated that the mechanism of apoptosis induced by phospha sugar derivatives not only to tumor cells of leukemia cell lines of U937 but also to tumor cells of various kinds of leukemia cell lines selectively to decrease the tumor cell viability of various kinds of leukemia cell lines. The Western blot analyses for phospha sugar DBMPP against U937 leukemia cell lines showed that the phospha sugar affected on the expressions of the factors of cell cycles in the manners of suppressing the expression of the accelerator factors of cell cycles of tumor cells and enhancing the expression of suppressor factors of cell cycles of tumor cells by the medications of phospha sugars. TBMPP enhanced the expression of IER5 and then suppressed the expression of Cdc25B, which is the common factor to accelerate the cell cycles of various kinds of tumor cells. Therefore, suppression of the expression of Cdc25B by TBMPP implies that the branched deoxybromophospha sugar derivatives might be novel and potential multiple type molecular targeted antitumor agents against various kinds of tumor cell lines. GRAPHICAL ABSTRACT

Preparation of Phospha Sugar Analogues and Their Evaluation as Novel Molecular Targeting Anticancer Agents

Abstract Phospha sugars were prepared by a novel synthetic route starting from phosphorus heterocyclic compounds, 2-phospholenes. The anhydro- and deoxy-phospha sugar derivatives have been revealed to have potential anticancer activities against human leukemia of K562 and U937 cell lines. In this article, deoxybromophospha sugars with different numbers of bromo substituents were prepared, and their anticancer activities were evaluated by MTT method. The order of the activities depending on the number of bromo substituent was first revealed, and trideoxytribromotetrofuranose type phospha sugar [2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide (4: TBMPPAO)] was the most active among these phospha sugars prepared. Diasteromers of dideoxydibromotetrofuranose-type phospha sugar [2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide (2: DBMPPAO)] were separated into four components, and the structure as well as the character of each component was assigned by spectral and chromatographic data as well as by MTT method.The deoxybromophospha sugars have higher antileukemia activity than Gleevec against U937 cells.

Synthesis of Some 1-Aryl-2,3-dibromophospholanes as Novel Anti-Cancer Agents

Novel phosphorus heterocyclic compounds, 3-methyl-l-(3-bromophenyl as well as some 3-substituted phenyl)-2phospholene 1-oxides (Id as well as lb, lc, and If), were synthesized from l-phenyl-2-phospholene 1-oxide la via 3methyl-l-(3-nitrophenyl)-2-phospholene 1-oxide (lb). l-(4-Bromophenyl)-2-phospholene le was prepared by Grignard coupling reaction of l-chloro-3-methyl-2-phospholene 1-oxide with 4-bromophenylmagnesium bromide. 2,3-Dfbromo3-methyI-l-arylphospholane 1-oxides (2a-2e) were prepared by the addition reaction of bromine to the C=C double bond of 2-phospholenes lale . The substituent effect of the phenyl group of the 1-aryl-phospho lanes 2 on the observed anti-proliferative effect against U937 leukemia cell lines evaluated by MTT in vitro methods showed that 2,3-dibromo3-methyl-l-(4-bromophenyl)phospholane (2e) was the most active among 2. These novel dibromophosphorus heterocyclic derivatives exhibit much higher anti-cancer activity than Gleevec® (molecular targeting chemotherapeutic agent) against U937 cells.

Preparation and Characterization of Phospha Sugar Analogues, 2,3-Dibromo-3-methyl-1- phenylphospholane 1-Oxide Derivatives, as Novel Anticancer Agents

The synthesis of new phospha sugar analogues or phosphorus heterocycles and their biological activities as novel anticancer agents are reported in this article. A 1,2-dibromo-1,2-dideoxy phospha sugar derivative, 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide (2), was prepared from 1-phenyl-3-methyl-2-phospholene 1-oxide (1), and the yield and ratio of diastereomers 2a to 2d were changed by a catalyst such as manganese(IV) oxide and manganese(II) bromide. The antitumor activities of the mixture of dibromides 2 and the separated diastereomeric components 2a to 2d of the dibromides were evaluated by MTT in vitro method against the human leukemia cell lines of K562 and U937. The results showed that all of the diastereomers 2a to 2d as well as the diastereomer mixture exert excellent anticancer activity, and moreover, among them, diastereomer 2d showed the highest antitumor activity. Supplemental materials are available for this article. Go to the publishers online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Novel Multiple Type Molecular Targeted Antitumor Agents: Preparation and Preclinical Evaluation of Low-Molecular-Weight Phospha Sugar Derivatives

GRAPHICAL ABSTRACT Abstract Phospha sugar derivatives of 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide and 2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide were synthesized from 2-phospholenes and evaluated by in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide method against leukemia cell lines, and then characterized by cell cycle analysis, Western blot analysis, and molecular docking simulation. Phospha sugar derivatives were revealed to be potential antitumor agents against leukemia cell lines such as U937 and K562. Cell cycle analysis indicated that phospha sugar derivatives induced apoptoses. Western blot analyses against U937 showed that phospha sugar derivatives regulate many mitotic regulators in cell cycle. Results of molecular docking simulation suggested that phospha sugar derivatives enter the pockets present in cell cycle and apoptosis-related proteins.

Preparation and Evaluation of Novel Sugar Dendritic Gd-DTPA Complexes for MRI Contrast Agents and Phospha Sugars for Anti-Tumour Agents

Novel Sugar Dendritic Gd(III)-DTPA complexes for MRI Contrast Agents (CAs) were prepared and evaluated by in vitro and in vivo methods. The sugar dendritic MRI contrast agents had a good blood vessel pool character and drew blood vessels and liver cancers remarkably clearer and longer time enough than the clinically being used Gd(III)-DTPA complex (Magnevist). Phospha sugar derivatives or phosphorus heterocyclic derivatives provided by functional groups such as epoxide, bromide, etc., were prepared and evaluated by the MTT in vitro method. These phospha sugar derivatives showed excellent anti-proliferative effects of leukemia cell lines, e.g., K562 and U937, as well as solid cancer cells in fashions of (i) higher activity, (ii) wider spectra, and (iii) higher selectivity and specificity than Imatinib mesylate (Gleevec), which is one of the most frequently used chemotherapeutical molecular targeting anti-tumour agent.